Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCKalpha kinases

Détails

ID Serval
serval:BIB_8E081E9B53E4
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCKalpha kinases
Périodique
Genes and Development
Auteur(s)
Lefort  K., Mandinova  A., Ostano  P., Kolev  V., Calpini  V., Kolfschoten  I., Devgan  V., Lieb  J., Raffoul  W., Hohl  D., Neel  V., Garlick  J., Chiorino  G., Dotto  G. P.
ISSN
0890-9369 (Print)
Statut éditorial
Publié
Date de publication
03/2007
Volume
21
Numéro
5
Pages
562-77
Notes
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't --- Old month value: Mar 1
Résumé
Little is known about the regulation and function of the Notch1 gene in negative control of human tumors. Here we show that Notch1 gene expression and activity are substantially down-modulated in keratinocyte cancer cell lines and tumors, with expression of this gene being under p53 control in these cells. Genetic suppression of Notch signaling in primary human keratinocytes is sufficient, together with activated ras, to cause aggressive squamous cell carcinoma formation. Similar tumor-promoting effects are also caused by in vivo treatment of mice, grafted with keratinocytes expressing oncogenic ras alone, with a pharmacological inhibitor of endogenous Notch signaling. These effects are linked with a lesser commitment of keratinocytes to differentiation, an expansion of stem cell populations, and a mechanism involving up-regulation of ROCK1/2 and MRCKalpha kinases, two key effectors of small Rho GTPases previously implicated in neoplastic progression. Thus, the Notch1 gene is a p53 target with a role in human tumor suppression through negative regulation of Rho effectors.
Mots-clé
Animals Carcinoma, Squamous Cell/*genetics/metabolism/pathology Cell Culture Techniques Cell Differentiation Cell Line, Tumor Down-Regulation *Genes, Tumor Suppressor Humans Intracellular Signaling Peptides and Proteins/*metabolism Keratinocytes/cytology/*metabolism Mice Protein-Serine-Threonine Kinases/*metabolism Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors RNA, Small Interfering Receptor, Notch1/*genetics/metabolism Signal Transduction Skin Neoplasms/genetics/metabolism/pathology Stem Cells/cytology Tumor Suppressor Protein p53/*metabolism Tumor Suppressor Proteins/genetics/metabolism
Pubmed
Web of science
Open Access
Oui
Création de la notice
24/01/2008 15:59
Dernière modification de la notice
08/05/2019 21:51
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